B-cell lymphomas express surface antigens that have shown to be good targets for therapy with monoclonal antibodies (Mab). Antibodies, either used alone (naked antibodies) or in conjunction with chemotherapy, can be conjugated with toxins or with radionuclides for radioimmunotherapy (RAIT). The radiolabelled antibody is administered after (Kaminski, M. S. et al., J. Clin. Oncol. 19:3918-3928, 2001) or together (Press, O. W. et al, New Engl. J. Med. 329:1219-24, 1993) with unlabelled antibody to improve dose distribution. Most investigators use a radiolabeled mouse antibody combined with an unlabeled antibody, which is murine or chimeric. It has been considered advantageous to radiolabel a mouse antibody from a toxicological point of view due to its shorter half-life compared to a chimeric antibody. A Mab with longer half-life gives a longer residence time of the radioimmunoconjugate in blood and bone marrow and probably thus induces more toxicity. Since the antibody in its own right hardly induces toxicity both mouse and chimeric unlabelled antibodies are used to improve dose distribution by allegedly saturating antigen on normal cells and tissues in the body (cf. Kaminski, U.S. Pat. No. 5,595,721; Wiseman et al., Crit. Rev. Oncol. Hematol. 39:181-194, 2001).
The use of monoclonal antibodies in targeted radiotherapy of cancers (radioimmunotherapy; RAIT) has produced striking clinical responses in hematologic diseases such as non-Hodgkin's lymphoma (NHL). New strategies are presently examined in an effort to minimize the systemic toxicity of a circulating radionuclide and the sensitization of tumors by radiation. The former being carried out by pretargeting and the latter by combination therapy with radiosenzitizing drugs. See Govindan, S. V et al., Current Trends, Pharmaceutical Science and Technology Today 3:90-98, 2000.
The anti-tumor activity of RAIT is mainly due to the associated radioactivity of the radiolabel attached to the antibody, which emits continuous, exponentially decreasing low-dose-rate irradiation with a heterogeneous dose deposition. Four radiolabeled antibody products are progressing towards commercialization for the RAIT of NHL. They include 131I-tositumomab (Bexxar™), 90Y-ibritumomab tiuxetan (Zevalin™), 90Y-epratuzumab (hLL2) and 131I-Lym-1. For a more detail review of these products, see Goldenberg, D. M., Critical Reviews in Oncology/Hematology 39:195-201, 2001, and Goldenberg, D. M., J. Nucl. Med. 43:693-713, 2002.
Bexxar (Corixa Corp., Seattle, Wash.) and Zevalin (IDEC-Y2B8; IDEC Pharmaceuticals, San Diego, Calif.) are both murine monoclonal antibodies (Mabs) directed against CD20 antigen expressed in the surface of normal and malignant B-lymphocytes. Bexxar is used as an IgG2a murine Mab with cold murine antibody added, whereas Zevalin has the murine antibody labeled and cold human.mouse chimeric rituximab (Rituxan™, IDEC-Genentech) added to the product. Both products provide for pretherapy cold antibody dosing in order to improve tumor targeting, which involves a 1-h infusion of 450 mg of unlabeled Bexxar antibody and a 4-6 h infusion of 450 mg of rituximab with Zevalin. Both products have shown a higher and more durable responses than naked antibodies, however, they also have dose-limiting toxicity, predominantly myelotoxicity. Zevalin was approved by the Food and Drug Administration (FDA) for the treatment of recurrent low grade or transformed B cell non-Hodgkin's lymphoma. These radiolabeled anti-CD-20 Mab must be preceded by a dose of cold antibodies to enable good tumor localization. In fact, the specific localization numbers for 111indium-Zevalin drop from 78% to 15% tumor uptake at specific tumor sites when predosing is involved (Wiseman et al., ibid).
Epratuzumab (90Y-epratuzumab) is a humanized IgG1 antibody directed against the anti-CD22 antigen. The antigen is fast internalized upon antibody binding. The naked antibody has been reported to show efficacy in follicular as well as diffuse large B-cell lymphoma (Leonard, J. P. et al., Epratuzumab (hLL2, anti-CD22 humanized monoclonal antibody) is an active and well-tolerated therapy for refractory/relapsed diffuse large B-cell non-Hodgkin's lymphoma (NHL). Blood (Suppl) 96:578a [abstr. 2482], 2000; Press, O. W. et al., Immunotherapy of Non-Hodgkin's Lymphomas. Hematology (Am. Soc. Hematol. Educ. Program), p. 221-40, 2001). Epratuzumab is not expected to give rise to human anti-human antibodies (HAHA), which makes it suited for repeated dosing. The mouse parental antibody, mLL2, labelled with 131I and has shown efficacy in various subtypes of B-cell lymphoma (Linden, O. et al. Clin. Cancer Res. 5:3287s-3291 s, 1999). After internalization, the 131I-labelled antibody is dehalogenated and the radionuclide is released from the cell. Radiometals like yttrium are retained in the cell upon internalization (Sharkey, R. M., et al. Cancer Immunol. Immunother. 44:179-88, 1997). The shorter physical half-life of 90Y compensates in some degree for the longer half-life of epratuzumab and provides the rational for their combination.
RAIT is usually given as a single infusion. There are, however, theoretical advantages of a fractionated approach, since fractionation would better deal with the problem of heterogeneity in absorbed dose, as outlined in O'Donoghue, J. A., Dosimetric Principles of Targeted Radiotherapy, in Radioimmunotherapy of Cancer, A. R. Fritzberg (ed.), Marcel Dekker, Inc., p. 1-20, New York, Basel, 2000. There are also experimental data supporting that therapeutic response can be improved by splitting a large single administration of radiolabelled antibody into a number of smaller administrations (Schlom, J. et al. J. Natl. Cancer Inst. 82:763-71, 1990). Approaches with two infusions as well as multiple have been explored clinically using mouse antibodies (DeNardo, G. L., et al. Cancer Biother. Radiopharm. 13:239-54, 1998; Vose, J. M., et al. J Clin. Oncol. 18:1316-23, 2000).
Intratumoral variability in the expression of CD22 antigen has been reported. In fresh tumor samples from five patients, 52-89% of lymphoma cells were found to bear the antigen for the anti-CD22 MAb HD6 (Press, O. W. et al. Cancer Res. 49:4906-12, 1989). One alleged advantage of RAIT using long range β-emitters is their ability to kill antigen negative tumour cells in the vicinity of the targeted cells. By assessing the antigen expression of tumour cells before therapy, one could study the clinical relevance of this concept in the setting of RAIT using the anti-CD22 90Y-labelled epratuzumab.
Research was undertaken to confirm the theoretical advantages of dose fractionation and the published experimental data that support it. The study was intended to investigate the feasibility of fractionated RAIT, using a radiolabeled humanized antibody. It was found that after predosing with 100 mg of the humanized CD22 Mab, epratuzumab, labelled with 111In for dosimetry purposes, subsequent fractionated doses of 90Y-labelled epratuzumab at doses of up to 7.5 mCi/m2, once weekly for up to 2-3 weeks, resulted in tolerable and effective radioimmunotherapy (Linden et al., Cancer Biother Radiopharm 2002; 17: 490 [abstract 47]. Although these clinical studies suggest that fractionated therapy of a radioimmunoconjugate is feasible, no comparison was made with administered a single high-dose of the radioimmunoconjugate in terms of safety and efficacy. Since the first “dosimetry” dose with 111In contained 100 mg of antibody, and each susccessive injection also contained this naked antibody dose, it also could not be determined if these doses that totalled at least 300 mg of epratuzumab also served as a predosing effect as suggested in other cited studies involving CD20 antibodies. Therefore, it was not interpretable from these studies whether or not any predosing was needed for such radioimmunotherapy, particularly with CD22 antibodies.
We have now found that predosing is not used in this invention, contrary to other published studies and Kaminski's U.S. Pat. No. 5,595,721, to saturate the antigenic sites in the normal tissues and spleen, as practiced in the prior art. Clearly, the invention disclosed herein shows that there is a lack of a need of high antibody predosing, as practiced in the prior art.